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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
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and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

(±)-Integrifolin

Total Synthesis of (±)-Integrifolin

Weight control is an important concern of human beings, both for medical (pharmaceutical and/or nutraceutical) as well as non-therapeutic, e.g. cosmetic, reasons. More importantly, excessive accumulation of body fat (i.e. obesity (= adiposity), especially with excessive fat in the ventral region and surrounding the viscera) can be dangerous and has been linked to health problems such as type II diabetes, hypertension, heart disease, atherosclerosis (where more than two of the preceding disorders are present, the condition is often called “Metabolic Syndrome” or “syndrome X”), hyperlipidemia, coronary heart disease, stroke, breast and colon cancer, sleep apnoea, gallbladder disease, reproductive disorders such as polycystic ovarian syndrome, gastroesophageal reflux disease, increased incidence of complications of general anesthesia, fatty liver, gout or thromboembolism (see, e.g., Kopelman, Nature 404: 635-43 (2000)). Obesity reduces life-span and carries a serious risk of the co-morbidities listed above, as well disorders such as infections, varicose veins,

acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen et al, Br. Med. J. 301 : 835-7 (1990)). Obesity is one of the main factors in the development of cardiovascular diseases. As a side effect the levels of cholesterol, blood pressure, blood sugar and uric acid in obese people are usually higher than those of persons of normal weight. The morbidity from coronary heart disease among the overweight people is increased as well. Among the people aged 40-50, mortality will rise about 1% when body weight increases by 0.5 kg and the death rate will increase 74% when body weight exceeds 25% of the standard. The prevalence of obesity in the United States has more than doubled since the turn of the last century (whole population) and more than tripled within the last 30 years among children aged from 6 to 11. This problem more and more becomes a disease risk also in Europe. In Germany, particularly many people have been found to suffer from overweight recently, already 25% of the young people, children and adolescents there are affected by obesity and related disorders. Furthermore, being overweight is considered by the majority of the Western population as unattractive.

Overweight and obesity result from an imbalance between the calories consumed and the calories used by the body. When the calories consumed exceed the calories burned, the body is in positive energy balance and over time weight gain will occur. The excess calories are stored in the fat cells. When the calories burned exceed the calories consumed, the body is in negative energy balance and over time weight loss will occur.

An increasing interest by consumers in the maintenance or reduction of their body weight can be found. This leads to a demand for products useful for these purposes. Preferred are such food products which can conveniently be consumed as part of the daily diet, for example meal replacer products, such as meal replacer bars and beverages. These are usually designed for use as a single-serving food product to replace one or two meals a day.

An issue is that often a saturating effect is missed when such products are consumed, resulting in hunger feelings only a relatively short time after consummation or even in the lack of a saturation feeling already directly after consummation.

Summing up, there remains a need for new safe and effective compositions for promoting weight loss and/or loss of body fat in subjects such as humans. The problem to be solved by the present invention is therefore to find compositions or compounds useful in the treatment of obesity; and/or for improving the total cholesterol HDIJLDL ratio.

Phytochemistry provides a large pool of compounds and compositions to be looked at whether they are able to solve this problem.

The present invention provides methods and compositions useful in the control, treatment and prevention of obesity and obesity-related conditions, disorders, and diseases; and/or and/or for improving the total cholesterol HDL/LDL ratio.

Rosinski, G., et al., Endocrinological Frontiers in Phyiological Insect Ecology, Wroclow Technical University Press, Wroclow 1989, describe that certain tricyclic sequiterpene lactones, such as grossheimin and repin, showed inhibition of larval growth and antifeeding activity in Mealworm (Tenebrio σιοΐϊίοή. Grossheimin shows no anti-feeding but little decrease of absorption of digested food constituents and a little decrease in efficiency in digesting. Repin exhibit low effects at all. Both compounds show no effect on lipid levels in blood.

Shimoda, H., et al, Bioinorganic & Medicinal Chemistry Letters 13 (2003), 223-228, describe that methanolic extracts from Artichoke (Cynara sclolymus L.) with cynaropicrin, aguerin B and grossheimin as components and certain sesquiterpene glycosides suppress serum triglyceride elevation in olive oil-loaded mice. Some of these compounds exhibit a moderate short term (2 hours after olive oil administration) anti-hyperlipidemic activity presented as a lowering of the serum triglyceride (serum TG) concentrations, the long term (6 hours) show in the case of cynaropicrin and aguerine B an increase of the serum TG. Furthermore the authors present data of the gastric emptying (GE) of a methanolic ectract of artichoke. They determine a significantly inhibited GE. However, as shown below, this mechanism is not an explanation for the anti obesity effect shown in the present invention (see Example 1 ).

Cynaropicrin, a tricyclic sesquiterpene lactone causes in vivo a strong weight loss. More surprisingly it was found that this effect is not correlated to a decrease in food intake. The weight balance is not affected by reduction of assimilation efficiency; the decrease of body fat and body weight is presumably caused by effects on energy metabolism. Surprisingly, it was found in addition that cynaropicrin also allows for improving the total cholesterol HDL7LDL ratio

Volutarella divaricata, Zaiuzania resinosa; and can potentially be isolated from any part of the plants. Those genera and/or species marked with an asterisk (*) and especially those species marked with two asterisks (**) are especially preferred.

Appropriate plant material can be obtained from various sources, e.g. from:

Beijing Shenogen Biomedical announced that Icaritin, a China Class I cancer drug, was granted Fast Track Review status after the company filed its New Drug Approval submission to the Beijing Food & Drug Administration. Icaritin is an oral traditional Chinese medicine, derived from barrenwort, which targets the estrogen receptor α36. Shenogen has conducted clinical trials of Icaritin in patients with liver cancer, though it expects the drug will also prove effective in breast cancer and other estrogen-related cancers as well. More details…. http://www.chinabiotoday.com/articles/20150917

Cardiovascular function improvement, hormone regulation and antitumor activity.
2. The anti-MM activity of Icaritin was mainly mediated by inhibiting IL-6/JAK2/STAT3 signaling.
3. The inhibitory activity of Icariside II on pre-osteoclast RAW264.7 growth was synergized by Icaritin, which maybe contribute to the efficiency of Herba Epimedii extract on curing bone-related diseases, such as osteoporosis.
4. The Icaritin at low concentration (4 or 8 μmol/L) can promote rat chondrocyte proliferation and inhibit cell apoptosis, while the effect of Icaritin on rat chondrocyte at high concentration was reversed.
5. Icaritin might be a new potent inhibitor by inducing S phase arrest and apoptosis in human lung carcinoma A549 cells.
6. Icaritin dose-dependently inhibits ENKL cell proliferation and induces apoptosis and cell cycle arrest at G2/M phase. Additionally, Icaritin upregulates Bax, downregulates Bcl-2 and pBad, and activates caspase-3 and caspase-9.

What is Epimedium ?

Herba epimedii (Epimedium, also called bishop’s hat, horny goat weed or yin yang huo), a traditional Chinese medicine, has been widely used as a kidney tonic and antirheumatic medicine for thousands of years. It is a genus of about 60 flowering herbs, cultivated as a ground cover plant and an aphrodisiac. The bioactive components in herba epimedii are mainly prenylated flavonol glycosides, end-products of the flavonoid pathway. Epimedium species are also used as garden plants due to the colorful flowers and leaves. Most of them bloom in the early spring, and the leaves of some species change colors in the fall, while other species retain their leaves year round.

Figure 1 Epimedium

Epimedium Raw Material

The herbs we used to extract icariin is one species of Epimedium, which name is Epimedium brevicornum Maxim. This kind of epimedium only can be abundantly found in Gansu province of China. And because of the growth habit of this kind of herb, which only grows under trees, it can’t to be planted, only can harvest the wild one.

This wild epimedium contains quite a bit of active components, depending on its long growth time and rich nutrient. Usually the content of the icariin is not lower than 1%.

Below photo is the herb specimen which we use. Picking in the epimedium full-bloom stage. And the medicinal value of the herb is the best at this time. The herb we select contains roots, stems, leaves and flowers. And we extract with the whole herb.

Figure 2 Epimedium for extract

Epimedium Extract

Epimedium extract is a herbal supplement claimed to be beneficial for the treatment of sexual problems such as impotence. It is believed to contain a number of active components, including plant compounds that may have antioxidant activity and estrogen-like compounds. The major components of Epimedium brevicornum are icariin, epimedium B and epimedium C. It is reported to have anti-inflammatory, anti-proliferative, and anti-tumor effects. It is also reported to have potential effects on the management of erectile dysfunction.

Figure 3 HPLC spectrum of icariin

Our specification available is Icariin HPLC 50%- 98%. Below please see the the information for reference:

Figure 4 Epimedium Extract(Icariin)

Derivatives

The plant extracts of epimedium traditionally used for male impotence, and the individual compounds is icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. The E. brevicornum extract and its active principle icariin were active. To improve its inhibitory activity, some derivatives ware subjected to various structural modifications, which include icaritin, icariside II and 3,7-bis(2-hydroxyethyl) icaritin. There have some scientific papers report that the improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make such compounds a promising candidate for further development. We hope that our new products can help you to find more commercial opportunity.

In this way, we can introduce those products as below, and we can also provide more details about the products according to your demand. The 1H-NMR of icaritin and 3,7-bis(2-hydroxyethyl) icaritin is as below.

Epimedium has been used to treat male erectile dysfunction in Traditional Chinese Medicine for many centuries. The main functions of Epimedium brevicornum in ancient Chinese books focused on the nourishment of kidney viscera and reinforcement of ‘yang’, resulting in the restoration of erectile function in males.

The novel total synthesis of icaritin (1), naturally occurring with important bioactive 8-prenylflavonoid, was performed via a reaction sequence of 8 steps including Baker-Venkataraman reaction, chemoselective benzyl or methoxymethyl protection, dimethyldioxirane (DMDO) oxidation, O-prenylation, Claisen rearrangement and deprotection, starting from 2,4,6-trihydroxyacetophenone and 4-hydroxybenzoic acid in overall yields of 23%. The key step was Claisen rearrangement under microwave irradiation. MS, 1H and 13C NMR techniques have been used to confirm the structures of all synthetic compounds. – See more at: http://www.eurekaselect.com/124334/article

The present invention relates to compositions comprising icariside I, and to a novel, one step method of preparing such compositions, comprising converting specific prenylated flavonol glycosides such as epimedium A, epimedium B, epimedium C, icariin, and their corresponding acetate derivatives contained in an Epimedium plant extract to a single compound, namely icariside I shown below as compound I, which was surprisingly discovered to be a strong PDE-5 inhibitor.

This invention further comprises compositions enriched for anhydroicaritin, and to methods of preparing such compositions. One method of this invention for preparing compositions enriched for anhydroicaritin comprises a one-step method of converting prenylated flavonol glycosides, specifically the sagittatoside compounds A, B, and C, and the corresponding acetate derivatives, present in Epimedium plant extracts to a single compound, namely anhydroicaritin shown below as compound II, which was also discovered to be a strong PDE-5 inhibitor.

EXAMPLES Example 1 Acid Hydrolysis of a 50% EtOH Extract and Purification by Reversed Phase ChromatographyWhole Epimedium grandiflorum leaves were extracted with a 1:1 mixture of ethanol and water at 55° C. The resulting extract (referred to as a “50% EtOH extract”) was filtered and the filtrate concentrated at 40-50° C. under vacuum and then dried under vacuum at 60° C. to a dry solid. The dried extract (131 g) containing approximately 5.8 g of total PFG’s was placed in a 2 liter round bottom flask and 1 L of 90% ethanol was added. The mixture was heated to reflux to help dissolve the solids. Concentrated sulfuric acid (28 mL) was added. The mixture refluxed for 2 hr, cooled to room temperature, and 900 mL of water added with stirring. Next the mixture was filtered using vacuum to remove insoluble sulfate salts and other solids and loaded on a 2.5×56 cm (275 mL) column packed with 250-600 micron divinylbenzene cross-linked polystyrene resin (Mitsubishi Chemical). The column was washed with 2 column volumes (CVs) of 60% ethanol and the icariside I was eluted with 2 CVs of 95% ethanol. The product pool was air-dried producing 11.3 g of brown solids. HPLC analysis (FIG. 5) showed that the solids contained 18% icariside I (peak 15.27 min) and 12% anhydroicaritin (peak 25.15 min). The recovery of the icariside I in the product pool was 87% of the amount present in the hydrolyzate.

Example 2 Purification of a Hydrolyzate by Liquid/liquid ExtractionThe ethanolic hydrolyzate (25 mL) prepared in Example 1 was mixed with 62.5 mL of de-ionized water and the pH was adjusted to 7.0 using 50% (w/w) sodium hydroxide solution. The resulting mixture was extracted with three 25 mL portions of ethyl acetate and the combined ethyl acetate extracts were back extracted with 150 mL of water. The ethyl acetate layers were combined, dried, and assayed for icariside I. HPLC analysis (FIG. 6) showed that the dried EtOAc fractions contained 22% icariside I (peak 15.29 min) and 11% anhydroicaritin (peak 25.27 min), and icariside I recovery into the ethyl acetate was 97% of the amount present in the hydrolyzate. The partition coefficient for icariside I between ethyl acetate and water was found to be 16, indicating that the icariside I has a high affinity for ethyl acetate over water.

Example 3 Acid Hydrolysis of a 50% EtOH Extract and Purification by PrecipitationThe dried extract (204 g) described in Example 1 was mixed with 1 L of 90% EtOH and then heated to reflux to help dissolve the solids. Sulfuric acid (25 ML) was added slowly with swirling. The mixture was refluxed 90 minutes and immediately chilled to stop the reaction. After cooling to room temperature, the mixture was filtered under reduced pressure through cellulose paper to remove insoluble sulfates and other materials, and the cake was washed with about 350 mL of 90% ethanol. The resulting ethanolic hydrolyzate (1.34 L) contained 4.1 g of icariside I.

The ethanolic hydrolyzate prepared above (1.32 L) was placed in a 10 L container and 40 g of 50% (w/w) sodium hydroxide solution was added followed by 20 mL of phosphoric acid. Next 3.3 L of deionized water was added with stirring. The pH of this mixture was 2.4. Sodium hydroxide solution (50% w/w ) was added until the pH was 8.25. The mixture was heated to 65° C. to assist with the coagulation of the precipitate. The mixture was cooled to room temperature and stirred for 0.5 hr at room temperature before filtering through a cellulose filter using vacuum. The resulting brown solids were washed with 715 mL of 10% ethanol and dried either under vacuum at room temperature or in air at 55° C. to yield brown solids. HPLC analysis (FIG. 7) showed the solids contained 20% icariside I (peak 15.27 min) and 10% anhydroicaritin. Recovery of icariside I using this precipitation procedure was 94% of the amount present in the hydrolyzate.

Example 4 Acid Hydrolysis of a Water Extract and Purification by PrecipitationGround Epimedium grandiflorum leaves (0.40 kg) were mixed with 5 L water in a 10 L round bottom flask. The flask was placed on a rotary evaporator for two hours at a rotation speed of 120 rpm and a water bath temperature of 90° C. The extract was filtered under reduced pressure through cellulose paper. The resulting filtrate (3.2 L) was evaporated using the rotary evaporator to a volume of 100 mL and dried under vacuum at 50° C.

The dark brown solids prepared above (40.4 g) were mixed with 200 mL of 90% ethanol and 6.0 mL of sulfuric acid in a 500 mL round bottom flask. The mixture was refluxed for 90 minutes and immediately chilled to stop the reaction. This mixture was filtered under reduced pressure through cellulose paper to remove insoluble sulfates and other materials. The cake was washed with 15 mL of 90% ethanol. The resulting ethanolic hydrolyzate (215 mL) contained 0.53 g of icariside I.

The hydrolyzate prepared above (50 mL) was transferred to a 250 mL beaker and 2.5 mL of 50% (w/w) sodium hydroxide solution was added with stirring to adjust the pH of the solution to pH 9, followed by 1.5 mL of concentrated phosphoric acid. Deionized water (125 mL) was added, and the mixture was adjusted to pH 8.2 using 1.5 mL of 50% sodium hydroxide solution. The mixture was heated to 65° C. to assist with coagulation of the precipitate and cooled to room temperature. The mixture was allowed to sit undisturbed at room temperature for 30 minutes prior to filtration under reduced pressure through cellulose paper. The resulting olive-green solids were washed with 25 mL of de-ionized water and dried under vacuum at room temperature or in air at 80° C. to produce olive-green solids. HPLC analysis (FIG. 8) showed the solids contained 60% icariside I (peak 15.33 min) and 2.4% anhydroicaritin (peak 25.40 min). Recovery of icariside I using this precipitation procedure was 92% of the amount present in the hydrolyzate.

Example 5 Enzymatic Hydrolysis of Icariside Ia) The substrate was a partially purified icariside I product with 20% icariside I and 11% anhydroicaritin. About 50 mg was dissolved in 10 mL of ethanol, and water or buffer was added until the mixture became cloudy (about 20% ethanol). The following dry enzymes were added to separate samples: α-amylase, α-glucosidase, β-amylase, β-glucosidase, hesperidinase, lactase, and pectinase. The samples were incubated overnight at 40 ° C. and analyzed by HPLC. The results were only semi-quantitative due to the difficulty in dissolving the anhydroicaritin that precipitated from the samples. However, several of the chromatograms did show a definite reduction in icariside I and increase in the ratio of anhydroicaritin to icariside I. The best results were obtained using hesperidinase, lactase, β-glucosidase and pectinase.

A larger scale experiment was done using hesperidinase in order to isolate pure anhydroicaritin for characterization. Pure icariside I (20 mg )was dissolved in 10 mL of ethanol and 50 mL of water and 200 mg of hesperidinase enzyme was added and the mixture was incubated for 24 hr at 40 ° C. Crude anhydroicaritin was collected via filtration and purified on a 2.5×30 cm semi-prep C-18 HPLC column using a gradient of 50:50 (MeCN/H2O) to 80:20 (MeCN/H2O) in 20 min. The pure anhydroicaritin was analyzed by LC/MS and proton NMR.

b) Enzymatic Hydrolysis of PFG’s: The purified PFG solids (55.3%, purified by reversed-phase chromatography of a 50% EtOH extract) were subjected to enzymatic hydrolysis with the same enzymes and conditions described in part (a). Hesperidinase, lactase, β-glucosidase and pectinase appeared to convert the mixture of PFG’s to a mixture of sagittatosides, but no icariside I or anhydroicaritin were observed. This indicated that these enzymes were specific for the 7-β-glucosyl group and did not hydrolyze the 3-position sugar(s).

Example 6 Preparation of a High Anhydroicaritin-containing ProductA high sagittatosides Epimedium sagittatum extract containing 24.7% total sagittatosides (assayed as icariin) and 8.1% icariin and other expected prenylated flavonol glycosides was obtained from China. A 50 g portion of this extract was mixed with 250 mL of 90% ethanol and 7.5 mL of concentrated sulfuric acid in a 500 mL round bottom flask. The mixture was refluxed for 90 minutes, then allowed to cool to room temperature. The hydrolyzed mixture was filtered under reduced pressure through cellulose paper to remove insoluble sulfates and other materials. The cake was washed with approximately 20 mL of 90% ethanol. The resulting filtered ethanolic hydrolyzate (305 mL) contained 3.75 g of anhydroicaritin and 2.50 g of icariside I.

The filtered hydrolyzate prepared above (200 mL) was transferred to a 1000 mL container and 8.0 mL of 50% (w/w) sodium hydroxide solution was added with stirring, followed by 4.0 mL of phosphoric acid. De-ionized water (500 mL) was then added. This mixture was adjusted to pH 4.9 using 50% sodium hydroxide solution. The mixture was allowed to sit undisturbed at room temperature for 24 hours prior to decanting off the liquid. The resulting solids were macerated using de-ionized water and filtered under reduced pressure through cellulose paper. The resulting dark brown solids (11.9 g) were washed with de-ionized water and dried in air overnight. The dark brown solids contained 20% anhydroicaritin and 12% icariside I and an anhydroicaritin/icariside I ratio of 1.66. The recovery of anhydroicaritin in the precipitation procedure was 94% from the hydrolyzate.

Example 7 Recrystallization of Icariside IIcariside 1 (30 mg) obtained by a method described in Example 1 was dissolved in a minimum of hot tetrahydrofuran (THF). Hot methanol (approximately 10 mL) was then added. The hot THF/MeOH solution was filtered through a PTFE filter into a vial and allowed to evaporate at room temperature to about 5 mL, whereupon crystals began to form, and then placed in a 4° C. refrigerator for 24 hours. The crystals were filtered and washed with cold methanol and dried in a vacuum. Icariside I (21 mg) was isolated as yellow crystals and had a chromatographic purity of 97.4%.

Example 8 Large Scale Acid Hydrolysis of an Epimedium extractAn 800 g portion of an Epimedium sagittatum powder extract obtained from China containing about 13% total prenylflavonol glycosides as icariin was mixed with 4.0 L of 90% ethanol and 120 mL of sulfuric acid in a 10 L round bottom flask. The mixture was refluxed for 90 minutes and immediately chilled to stop the reaction. This mixture was filtered under reduced pressure through cellulose paper to remove insoluble sulfates and other materials. The cake was washed with approximately 200 mL of 90% ethanol. The resulting ethanolic hydrolyzate (4.0 L) contained 33.7 g of icariside I.

The ethanolic hydrolyzate prepared above was transferred to a 34 L container and 200 mL of 50% (w/w) sodium hydroxide solution was added with stirring, followed by 120 mL of phosphoric acid. De-ionized water (10 L) was then added. This mixture was adjusted to pH 8.2 using 120 mL of 50% sodium hydroxide solution. The mixture was stirred for 10 minutes and allowed to sit undisturbed at room temperature for 60 minutes prior to filtration under reduced pressure through cellulose paper. The resulting olive-green solids were washed with 750 mL of de-ionized water and dried under vacuum at 50° C. or in air at 80° C. The olive-green solids contained 44.6% icariside I. Recovery of icariside I in the precipitation procedure was 96% from the hydrolyzate.

Example 9 Large Scale Purification of an Epimedium Extract Containing Prenylflavonoid GlycosidesA 3.7 kg portion of an Epimedium sagittatum powdered extract obtained from China containing approximately 10% total prenylflavonol glycosides (PFG’s) assayed as icariin was stirred with 35 L of 85/15 acetone/water (v/v) in a 50 L mixing tank. The mixture was stirred vigorously for 30 minutes and allowed to sit for 5 minutes. The acetone extract layer (36 L) was decanted from the tank and contained 362 g of PFG’s. Recovery of the PFG’s in this extraction procedure was 96%.

A portion (about 500 mL) of the acetone extract was dried under reduced pressure at 50° C. or less, providing 16.1 g of brown solids which were analyzed to contain 28.6% total PFG’s when assayed as icariin.

ROCHESTER, Minn. — High doses of the herb American ginseng (Panax quinquefolius) over two months reduced cancer-related fatigue in patients more effectively than a placebo, a Mayo Clinic-led study found. Sixty percent of patients studied had breast cancer. The findings are being presented at the American Society of Clinical Oncology’s annual meeting.

Researchers studied 340 patients who had completed cancer treatment or were being treated for cancer at one of 40 community medical centers. Each day, participants received a placebo or 2,000 milligrams of ginseng administered in capsules containing pure, ground American ginseng root.

“Off-the-shelf ginseng is sometimes processed using ethanol, which can give it estrogen-like properties that may be harmful to breast cancer patients,” says researcher Debra Barton, Ph.D., of the Mayo Clinic Cancer Center.

At four weeks, the pure ginseng provided only a slight improvement in fatigue symptoms. However, at eight weeks, ginseng offered cancer…

Like this:

Gastric (Stomach) cancer is a particularly deadly form of cancer that has a very poor prognosis in most cases. Worldwide over 700,000 people will die from stomach cancer and less than 10% of the people diagnosed with stomach cancer will survive. Because of these statistics, researchers are continually looking for anything that can provide a better outcome.

Recently a team of researchers from Shanghai University conducted a study exploring a traditional Chinese Herbal Formula called Zuo Jin Wan on stomach cancer cells. The formula itself is quite basic compared to many in the materia medica with only two ingredients -Huang Lian and Whu Zhu Yu (ina 6:1 ratio). In TCM it is primarily used for what we would call liver fire leading to rebellious qi – which in some cases could be rephrase so to speak as poor diet and emotional stress leading to reflux.

BOSTON, Mass. (February 12, 2012)—For roughly two thousand years, Chinese herbalists have treated Malaria using a root extract, commonly known as Chang Shan, from a type of hydrangea that grows in Tibet and Nepal. More recent studies suggest that halofuginone, a compound derived from this extract’s bioactive ingredient, could be used to treat many autoimmune disorders as well. Now, researchers from the Harvard School of Dental Medicine have discovered the molecular secrets behind this herbal extract’s power.

It turns out that halofuginone (HF) triggers a stress-response pathway that blocks the development of a harmful class of immune cells, called Th17 cells, which have been implicated in many autoimmune disorders.

“HF prevents the autoimmune response without dampening immunity altogether,” said Malcolm Whitman, a professor of developmental biology at Harvard School of Dental Medicine and senior author on the new study. “This compound…

A Chinese herb called thunder god vine works better than a widely-prescribed pharmaceutical drug at easing rheumatoid arthritis, a new study has found.

The herb has long been used in China to treat this potentially crippling autoimmune disease, which typically strikes hand and foot joints. It is known in Mandarin as ‘lei gong teng’ and to botanists as Tripterygium wilfordiiHook F.

Extracts of the herb have already fired the interest of drug laboratories as they contain hundreds of compounds, including intriguing molecules called diterpenoids which are believed to ease inflammation and immune response.

Researchers at the Johns Hopkins School of Medicine have discovered that a natural constituent isolated from a traditional Chinese medicinal herb, Triptergium wilfordii Hook F. (雷公藤, Lei Gong Teng, Thunder God Vine), used for hundreds of years to treat many conditions, works well by blocking gene control machinery in the cell. Thunder God Vine (Lei Gong Teng) is regarded as toxic and used externally to treat rheumatoid arthritis and sciatica. This report, published as a cover story of the March issue of Nature Chemical Biology, suggests that the natural constituent could be a starting point for developing new anti-cancer drugs.

The extracts of Triptergium wilfordii have been used to treat a whole host of conditions and highly lauded for anti-inflammatory, immunosuppressive, contraceptive and anti-tumor activities. The researchers have known about the active compound, triptolide, which can stop cell growth, since 1972, but only now have they figured out what it does.

Triptolide, the active ingredient purified from Tripterygium wilfordii, has been shown in animal models to be effective against cancer, arthritis, and skin graft rejection. In fact, triptolide has been shown to block the growth of all 60 U.S. National Cancer Institute cell lines at very low doses, and even causes some of those cell lines to die. Other experiments have suggested that triptolide interferes with proteins known to activate genes, which gives the researchers an entry point into their research. Using information already known about these proteins and testing the rest to see if triptolide would alter their behaviors, the research team finally found that triptolide directly binds to and blocks the enzymatic activity of a protein.

Triptolide’s general ability to stop enzymatic activity explains its anti-inflammatory and anticancer effects. And its behavior has important additional implications for circumventing the resistance that some cancer cells develop to certain anti-cancer drugs. The researchers are eager to study it further to see what it can do for future cancer therapy.

Triptolide, a diterpene triepoxide, is a major active component of extracts derived from Tripterygium wilfordii. Triptolide has multiple pharmacological activities including anti-inflammatory, immune modulation, antiproliferative and proapoptotic activity.[2]

The Chinese herb, Lei Gong Teng, comes from the roots, leaves and flowers of the tripterygium wilfordii Hook. f. It is collected during summer and autumn. Tripterygium wilfordii Hook is a deciduous climbing vine growing to 12 meters, with brown, angular, downy twigs. The leaves are light green, smooth on top, and pale gray with light hairs underneath. They have crenate margins and pointed apexes, and are ovate to elliptic, 5-15 cm long, 2.5 – 7 cm wide. The scented hermaphroditic (having male and female organs) flowers, which bloom in September, are small and whitish with five petals and are about 9 mm across, in terminal panicles in July. The fruit is 3-winged, and brownish red, about 1.5 cm long. The plant can grow in light (sandy), medium (loamy) and heavy (clay) soils. It can survive in acid, neutral and basic (alkaline) soil. It can grow in semi-shade (light woodland) or no shade. It requires moist soil.

Reduction of male fertility

The plant contains many active compounds, at least six of which have male anti-fertility effect (triptolide, tripdiolide, triptolidenol, tripchlorolide, 16-hydroxytriplide and a compound known as T7/19, whose structure is unpublished). The mechanism by which they affect fertility is not yet understood. What is known is that daily doses of these compounds reduce sperm counts and also severely affect the formation and maturation of sperm, causing them to be immotile.

Scientific research into medical effects

Contraception

Certain extracts from Tripterygium wilfordii, as well as from Tripterygium hypoglaucum (now considered identical to T. regelii) and Tripterygium regelii, were discovered in the 1980s to have temporary antifertility effects, which has led to research on its potential as a contraceptive.

“Tripterygium wilfordii Hook.f., known as Leigongteng (Thunder God Vine) in traditional Chinese medicine, has attracted much attention for its applications in relievingautoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus, and for treating cancer. Molecular analyses of the ITS and 5S rDNA sequences indicate that T. hypoglaucum and T. doianum are not distinct from T. wilfordii, while T. regelii should be recognized as a separate species. The results also demonstrate potential value of rDNA sequence data in forensic detection of adulterants derived from Celastrus angulatus in commercial samples of Leigongteng.”[3]

Not enough is known about T. wilfordii to actually test it as a contraceptive. Research thus far has dealt with establishing the mechanism by which the plant affects fertility, and investigating toxicity and side effects. What has been learned is encouraging, however: in both animals and humans, low doses of various Tripterygium extractscan produce significantly lowered sperm density and motility indices without major side effects. When the treatment was ended in the various trials, all indices returned to normal within months.

T. wilfordii could be an effective pharmaceutical alternative to contraceptives based on hormonal manipulation.

Kidney function

As of 2012 The Nanjing University School of Medicine is conducting a clinical trial of Tripterygium wilfordii to determine its possible beneficial effects on kidney volume and kidney function for polycystic kidney disease (PKD) patients.[4] It should report in late 2013.[dated info]

Immunosuppression

A small molecule Triptolide derived from T. wilfordii has been shown to disrupt mitochondrial function in cells and is under investigation as an anti-tumor agent or to suppress auto-immune disorders.

Rheumatoid arthritis

In China Tripterygium wilfordii has an established history of use in the treatment of rheumatoid arthritis. The herb shows immunosuppressive, cartilage protective, and anti-inflammatory effects.[5][6] The National Center for Complementary and Alternative Medicine has noted that one systematic review of the literature found that Tripterygium wilfordii may improve some RA symptoms, though another systematic review has stated that the serious side effects occur frequently enough to make the risks of taking this herbal supplement too high for the possible benefits.[7]

Pancreatic cancer

Drugs derived from the plant also show potential for reduction and elimination of pancreatic tumors in mice. Clinical trials may soon begin for the development of a drug for use in humans.[9]

At medicinal doses, T. wilfordii extract does have significant side effects, including immunosuppression. However, this may not apply to contraceptive use. Many of the side effects are caused by the other active compounds found in the plant, and do not appear when a pure extraction of its compounds with anti-fertility effect is used. In addition, the dose required to lower fertility is significantly lower than the standard medicinal dose.

In August 2011, the UK Medicines and Healthcare products Regulatory Agency (MHRA) published a drug safety bulletin advising consumers not to use medicines containing Lei Gong Teng. This was due to concerns over potentially serious side effects.

However, a recent review stated that although Tripterygium wilfordii has toxic potential, careful extraction gives an acceptable frequency of adverse reactions, which are largely related to the gastrointestinal tract and amenorrhea. The review found that T. wilfordii extract is useful remedy for postmenopausal rheumatoid arthritis.[11]

The Beijing TV series of China Medicine has shown people being treated successfully with the herb in a formula for rheumatoid arthritis. and outlined some practice to alleviate problems of using the herb. As often the case of TCM, formulations need to to be adjusted for individual’s physiology for best result.

PG490-88 (14-succinyl triptolide sodium salt) is a semisynthetic compound derived from the diterpene triepoxide, triptolide (PG490). PG490 was first isolated and structurally characterized in 1972 when it was extracted from the Chinese medicinal herb, Tripterygium wilfordii Hook F (TWHF), a member of the Celastraceae family. Historically, extracts of TWHF have been used for centuries in traditional Chinese medicine but in the 1970s, they were identified as being effective in the treatment of inflammatory/autoimmune disorders such as rheumatoid arthritis. Since then, more rigorous attempts were made to better identify biologically active constituents of TWHF responsible for its various clinical properties. We now know, for example, that diterpenoid components of TWHF, especially PG490, exert their anti-inflammatory and immunosuppressant effects by inhibition of cytokine production (e.g. , IL-2, IL-4, IFN) by T lymphocytes. These effects of PG490 have also been explored in mouse models where it was shown that PG490 prevents graft versus host disease (GVHD) and prolongs skin, heart, and kidney allograft survival.

The isolation of PG490 has also led to studies supporting its potential development as an antineoplastic agent. Shamon et al., for example, showed that PG490 inhibited growth of several human cancer-derived cell lines (including breast, prostate, and lung) grown in culture. PG490 was also shown to induce apoptosis of human promyelocytic leukemia, T-cell lymphoma, and hepatocellular carcinoma cell lines grown in culture. Interestingly, the inhibitory effects of PG490 on the growth of tumor cells in culture were enhanced in the presence of other inducers of apoptosis such as tumor necrosis factor- (TNF) and chemotherapeutic agents. When combined with chemotherapeutic drugs, PG490 enhanced apoptosis through signaling pathways involving both p53 and p21.

Data on the effects of PG490 on tumor cell growth in vivo , however, are limited. Previous reports have shown that PG490 inhibits tumor development in a hamster model of cholangiocarcinoma and in a murine breast cancer model. These beneficial effects of PG490, however, were counterbalanced by toxicity that was observed at high doses. In the present studies, we further examined the role of PG490 in inhibition of tumor cell growth both in vitroand in a tumor xenograft model. We show that PG490-88, a water-soluble prodrug of PG490, suppresses tumor cell growth in vivo without toxicity. We also show that PG490 acts in synergy with chemotherapy. Our results suggest a potential role of PG490-88 alone and in combination with chemotherapy as a novel antineoplastic regimen for the treatment of patients with solid tumors

The molecular target(s) for PG490 is currently unknown. Clues to the cellular target, however, are emerging from its effect on transcriptional activity. For example, we have shown along with Qiu et al. , that PG490 blocks transcriptional activation of NF- B by blocking transcriptional activation of p65 but without affecting DNA binding by p65. Additionally, we have found that PG490 blocks transcriptional activation by AP-1 and p53 without affecting DNA binding by Jun/Fos or p53. Recent studies show that the transcriptional activity of AP-1, NF-B, and p53 is regulated by a chromatin structure that is controlled, in part, by histone acetylation. In support of this, a recent study showed that p65 interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate NF- B transcriptional activity. Also, silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) was shown to inhibit transactivation of AP-1, NF-B, and serum response factor (SRF) by binding to their cognate transcription factors. Recent studies also show that p53-mediated transcriptional activity is regulated by histone acetylation. However, we have not observed an effect of PG490 on histone acetyltransferase (HAT) activity or histone acetylation.

PG490 at doses of 5–10 ng/ml does not repress basal transcriptional activity mediated by AP-1, NF-B, and p53 but it does block induction of NF-B by TNF and p53 transcriptional activity induced by chemotherapy. Also, PG490 does not affect topoisomerase I or II activity or increase topoisomerase cleavage complexes. Therefore, its synergy with chemotherapy may in large part be due to its inhibition of p21 mediated growth arrest, which activates an apoptotic pathway.

The treatment of solid tumors is evolving to more targeted treatments that may be helped by genetic profiling of tumors and targeting tumor-specific angiogenic and growth factor pathways. Also, several recent studies have shown that disrupting checkpoints in tumors drives tumor cells into apoptosis by abrogating checkpoint arrest. Here we show that PG490-88, a water-soluble derivative of PG490, reduces tumor growth, induces marked regression, or completely eradicates human tumor xenografts. Moreover, PG490-88 is a potent and well-tolerated antitumor agent that acts in synergy with DNA damaging agents and is effective in a clinically relevant dosing schedule. PG490-88 is now in phase I clinical trials for patients with solid tumors. A recent study showing that PG490 inhibits metastasis of solid tumors coupled with our findings that PG490-88 markedly enhances the cytotoxicity of DNA damaging agents suggests that PG490 or PG490-88 alone or in combination with chemotherapy may become an effective therapy for patients with solid tumors. Also, our finding that PG490 sensitizes tumor cells to TNF by blocking NF-B suggests a role for the combination in treating patients with TNF sensitive tumors such as melanoma. Identification of the target of PG490 and its mechanism of action will complement the ongoing clinical trials, and will provide insight into potential mechanisms of toxicity and the design of compounds that may be more selective and more potent.

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A Chinese herb called thunder god vine works better than a widely-prescribed pharmaceutical drug at easing rheumatoid arthritis, a new study has found.

The herb has long been used in China to treat this potentially crippling autoimmune disease, which typically strikes hand and foot joints. It is known in Mandarin as ‘lei gong teng’ and to botanists as Tripterygium wilfordiiHook F.

Extracts of the herb have already fired the interest of drug laboratories as they contain hundreds of compounds, including intriguing molecules called diterpenoids which are believed to ease inflammation and immune response.

In a study published in the journal Annals of the Rheumatic Diseases, Chinese researchers recruited 207 patients with rheumatoid arthritis and gave them either the herb; the drug methotrexate; or a combination of the two.

After six months, the patients were given a doctor’s assessment and were also asked if they felt…

Pin yin description:tu is a character for this herb derived from the character meaning rabbit; si means silk, and zi means seeds, the part used; this plant is a parasitic weed that sets up a mat of hair-like fibers at its base and then rapidly sends fibrous stems upward; thus Tu Si refers to the quality of these fibers like silky rabbit hair; a common name for dodders in the West, based on the undesirable weed-like nature of these plants, is Devil’s Hair.
Part use:Dodder seed,Aerial parts.(whole plants are harvested in autumn when the seeds are ripe, and then threshed after dried to get the seeds)

Habitat:Dodder grows throughout Europe, Asia, and southern Africa. Dodder prefers coastal and mountainous regions, and is gathered in summer.In China,mainly distributed in Jiangsu,Liaoning, Jilin, Hebei, Shandong and Henan provinces of China.
Taste:Pungent, Sweet,It is sweet in taste, warm in nature and manifests its therapeutic actions in the liver, kidney and spleen meridians.

Cuscuta , or Dodder plant, is a parasitic vine that wraps around other plants for nourishment.The ripe seed of Cuscuta chinensis Lam.; an annual voluble parasitic herb of the family Convolvulaceae.Cuscuta seed is used in China for kidney deficiency. Cuscuta has a high content of flavonoids and has strong antioxidant properties. Cuscuta seed has been found in studies to have positive effects on sperm health and motility, and invigorates the reproductive system.

Ophiocordyceps sinensis (left) growing out of the head of a dead caterpillar

Ophiocordyceps sinensis is a fungus that parasitizes larvae of ghost moths and produces a fruiting body valued as an herbal remedy. The fungus germinates in the living larva, kills and mummifies it, and then the stalk-like fruiting body emerges from the corpse. It is known in English colloquially as caterpillar fungus, or by its more prominent foreign names (see below): yartsa gunbu or yatsa gunbu (Tibetan), or Dōng chóng xià cǎo (Chinese: 冬虫夏草; literally “winter worm, summer grass”). Of the various entomopathogenic fungi, Ophiocordyceps sinensis is one that has been used for at least 2000 years[2] to treat many diseases related to lungs, kidney, and also used as a natural Viagra. This fungus is not yet cultivated commercially,[3] despite the fact that several fermentable strains of Ophiocordyceps sinensis are isolated by Chinese Scientists.[4] Overharvesting and over exploitation have led to the classification of O. sinensis as an endangered species in China.[5] Additional research needs to be carried out in order to understand its morphology and growth habit for conservation and optimum utilization.

The moths in which O. sinensis grows are ambiguously referred to as “ghost moth”, which identifies either a single species or the genus Thitarodes, and the species parasitized by O. sinensis may be one of several Thitarodes that live on the Tibetan Plateau (Tibet, Qinghai, West-Sichuan, SW-Gansu & NW Yunnan), and the Himalayas (India, Nepal, Bhutan).

O. sinensis is known in the West as a medicinal mushroom, and its use has a long history in Traditional Chinese medicine as well as Traditional Tibetan medicine.[6] The hand-collected fungus-caterpillar combination is valued by herbalists and as a status symbol;[7] it is used as an aphrodisiac and treatment for ailments such as fatigue and cancer, although such use is mainly based on traditional Chinese medicine and anecdote. Recent research however seems to indicate a variety of beneficial effects in animal testing, including increased physical endurance through heightened ATP production in rats.[8]

Cordyceps Sinensis

Cordyceps sinensis (Berk.) Sacc. and the usually the larvae are the remains of Hepialus varians

tonifies lung yin and kidney yang. For impotence, chronic lower back pain, afraid of cold, over abundance of mucus and tears, chronic cough and wheezing from deficiency, blood in phlegm from consumption due tokidney yang deficiency (shenyangxu).

improves auto-immune system function. It is an effective adjuvant therapy in hematopoietic dysfunction and in cancer. Cordyceps polysaccharide on peripheral blood lymphocytes possesses bidirectional immuno-modulatory effects.
It can enhance the macrophage immune activity.
Significant improvement of the condition of deformability of erythrocyte after strenuous exercise, and it is related to the degree of concentration of the extract of the herb. As the concentration increases, the effect of improvement increases.
It can significantly inhibit lipid peroxidation of membrane lipid peroxidation after exercise. There is a strong scavenging effect.

protects kidneys from toxins,

protects kidneys from exhaustion,

protects liver from toxins and treats and prevents cirrhosis of liver,

protect the heart from the damaging effect of ouabain(C29H44O12.8H2O),

anti-arrhythmia,

anti-rejection effect in cornea transplant,

antibiotic effect,

inhibits contraction of smooth muscles.

inhibits group A Streptococcus bacteria

Cordyceps ( Dong Chong Cao ) 冬蟲草 use in large dosages and/or long term usage can be toxic to kidneys.

According to the classics Medical Material, “Ben Cao Bei Yao” 本草備要, the best dong chong xia cao 冬蟲夏草, are produced in Sichuan. Today, most of them are produced in Xizang (Tibet) and Qinghai. Because the sizes the larvae are larger, they fetch higher prices.

According to the classics Medical Material, “Ben Cao Bei Yao” 本草備要, the best dong chong xia cao 冬蟲夏草, are produced in Sichuan. Today, most of them are produced in Xizang (Tibet) and Qinghai. Because the sizes the larvae are larger, they fetch higher prices.

Taxonomic History/ Systematics

Caterpillars with emergingOphiocordyceps sinensis

Morphological Features

Similar to other Cordyceps]] species, O. sinensis consists of two parts, a fungal endosclerotium (caterpillar) and stroma.[2] The stroma is the upper fungal part and is dark brown or black, but can be a yellow color when fresh and, longer than the caterpillar itself, usually 4–10 cm. It grows singly from the larval head, and is clavate, sublanceolate or fusiform and distinct from the stipe.[9] The stipe is slender, glabrous, and longitudinally furrowed or ridged. The fertile part of the stroma is the head. The head is granular due to the ostioles of the embedded perithecia.[2] The perithecia are ordinally arranged and ovoid [9] The asci are cylindrical or slightly tapering at both ends, and may be straight or curved, with a capitate and hemispheroid apex and may be two to four spored.[2] Similarly, ascospores are hyaline, filiform, multiseptate at a length of 5-12 um and subattenuated on both sides.[9] Perithecial, ascus and ascospore characters in the fruiting bodies are the key identification characteristics of O. sinensis. Ophiocordyceps (Petch) Kobayasi species produce whole ascospores and do not separate into part spores which is different from other Cordyceps species, which produce either immersed or superficial perithecia perpendicular to stromal surface and the ascospores at maturity are disarticulated into part spores.[10] Generally Cordyceps species possess brightly colored and fleshy stromata, but O. sinensis had dark pigments and tough to pliant stromata, a typical characteristic feature of most of the Ophiocordyceps species.[3]

Important developments in Classification

The species was first described scientifically by Miles Berkeley in 1843 as Sphaeria sinensis;[11]Pier Andrea Saccardo transferred the species to the genus Cordyceps in 1878.[12]The scientific name‘s etymology is from the Latincord “club”, ceps “head”, and sinensis “from China“. The fungus was known as Cordyceps sinensis until 2007, when molecularanalysis was used to emend the classification of the Cordycipitaceae and the Clavicipitaceae, resulting in the naming of a new family Ophiocordycipitaceae and the transfer of several Cordyceps species to Ophiocordyceps.[10] Based on a molecular phylogenetic study, Sung et al. (2007) separated the megagenus Cordyceps into four genera as it was polyphyletic, viz. Cordyceps (40 spp.), Ophiocordyceps (146 spp.), Metacordyceps (6 spp.) and Elaphocordyceps (21 spp.), while the remaining 175 spp. were left in Cordyceps. As a result, C. sinensis was transferred to Ophiocordyceps, hence renamed as O. sinensis.[2]

In Tibetan it is known as དབྱར་རྩྭ་དགུན་འབུ་ (ZYPY: yartsa gunbu, Wylie: dbyar rtswa dgun ‘bu, “summer grass winter bug”), which is the source of the Nepali यार्शागुम्बा, yarshagumba,yarchagumba or yarsagumba. The transliteration in Bhutan is Yartsa Guenboob. It is known as keera jhar, keeda jadi, keeda ghas or ‘ghaas fafoond in Hindi. Its name in Chinese Dōng chóng xià cǎo (冬蟲夏草) means “winter worm, summer grass” (i.e., “worm in the winter, [turns to] plant in the summer”). The Chinese name is a literal translation of the original Tibetan name, which was first recorded in the 15th Century by the Tibetan doctor Zurkhar Namnyi Dorje. In colloquial Tibetan Yartsa gunbu is often shortened to simply “bu” or “yartsa”.

Strangely, sometimes in Chinese English language texts Cordyceps sinensis is referred to as aweto [Hill H. Art. XXXVI: The Vegetable Caterpillar (Cordiceps robertsii). Transactions and Proceedings of the Royal Society of New Zealand 1868-1961. Vol 34, 1901;396-401], which is the Māori name for Cordyceps robertsii, a species from New Zealand.

The English term “vegetable caterpillar” is a misnomer, as no plant is involved. “Caterpillar fungus” is a preferable term.

Nomenclature of the anamorph

Since the 1980s, 22 species in 13 genera have been attributed to the anamorph of O. sinensis. Of the 22 species, Cephalosporium acreomonium is the zygomycetous species ofUmbelopsis, Chrysosporium sinense has very low similarity in RAPD polymorphism, hence it is not the anamorph. Likewise, Cephalosporium dongchongxiacae, C. sp.sensu,Hirsutella sinensis and H. hepiali and Synnematium sinnense are synonymous and only H. sinensis is only validly published in articles. Cephalosporium sinensis possibly might be synonymous to H. sinensis but there is lack of valid information. Isaria farinose is combined to Paecilomyces farinosus and is not the anamorph. Several species like Isaria sp. Verticella sp. Scydalium sp.Stachybotrys sp. were identified only up to generic level, and thus it is dubious that they are anamorph. Mortierella hepiali is discarded as anamorph as it belongs to Zygomycota. Paecilomyces sinensis and Sporothrix insectorum are discarded based on the molecular evidence. P. lingi appeared only in one article and thus is discarded due to incomplete information. Tolypocladium sinense, P. hepiali, and Scydalium hepiali, have no valid information and thus are not considered as anamorph toOphiocordyceps sinensis. V. sinensis is not considered anamorph as there is no valid published information. Similarly, Metarhizium anisopliae is not considered anamorph as it has widely distributed host range, and is not restricted only in high altitude.[13] Thus Hirsutella sinensis is considered the validly published anamorph of O. sinensis. Cordyceps nepalensis and C. multiaxialis which had similar morphological characteristics to C. sinensis, also had almost identical or identical ITS sequences and its presumed anamorph, H. sinensis. This also confirms H. sinensis to be anamorph of O. sinensis and suggests C. nepalensis and C. multiaxialis are synonyms.[14] Evidence based on microcyclic conidiation from ascospores and molecular studies [2] support H. sinensis as the anamorph of the caterpillar fungus, O. sinensis.

Ecology

The caterpillars prone to infection by O. sinensis generally live 6 inches underground [4] in alpine grass and shrub-lands on the Tibetan Plateau and the Himalayas at an altitude between 3,000 and 5,000 m (9,800 and 16,400 ft). The fungus is reported from the northern range of Nepal, Bhutan, and also from the northern states of India, apart from northern Yunnan, eastern Qinghai, eastern Tibet, western Sichuan, southwestern Gansu provinces.[4] The fungus consumes its host from inside out as they hibernate in alpine meadows. Usually the larvae are more vulnerable after shedding their skin, during late summer. The fungal fruiting body disperses spores which infect the caterpillar. The infected larvae tend to remain vertical to the soil surface with their heads up. The fungus then germinates in the living larva, kills and mummifies it, and then the stalk-like fruiting body emerges from the head and the fungus finally emerges from the soil by early spring.[15] Fifty-seven taxa from seven genera (1 Bipectilus, 1 Endoclita, 1 Gazoryctra, 12 Hepialus, 2Magnificus, 3 Pharmacis, and 37 Thitarodes[3]) are recognized as potential hosts of O. sinensis.

Reproduction Biology

Ophiocordyceps sinensis has both teleomorphic and anamorphic phases. Spending up to five years underground before pupating, the Thitarodes caterpillar is attacked while feeding on roots. It is not certain how the fungus infects the caterpillar; possibly by ingestion of a fungal spore or by the fungus mycelium invading the insect through one of the insect’s breathing pores. The dark brown to black fruiting body (or mushroom) emerges from the ground in spring or early summer, the long, usually columnar fruiting body reaches 5–15 cm above the surface and releases spores.

In late autumn, chemicals on the skin of the caterpillar interact with the fungal spores and release the fungal mycelia, which then infects the caterpillar.[4] After invading a host larva, the fungus ramifies throughout the host and eventually kills it. Gradually the host larvae become rigid due to the production of fungal sclerotia. Fungal sclerotia are multihyphal structures that can remain dormant and then germinate to produce spores. After over-wintering, the fungus ruptures the host body, forming a sexual sporulating structure (a perithecial stroma) from the larval head in summer that is connected to the sclerotia (dead larva) below ground and grows upward to emerge from the soil.[16] The slow growing O. sinensis grows at a comparatively low temperature, i.e., below 21oC. Temperature requirements and growth rates are crucial factors that identify O. sinensis from other similar fungi.[3]

Use in medicine

It is used as a curative to many diseases, anti- aging,[17] hypoglycemic,[18] aphrodisiac and also treatment against cancer. Ophiocordyceps sinensis serves against kidney and lung problems and stimulates the immune system; it is used for treatment of fatigue, night sweating, respiratory disease, hyperglycemia, hyperlipidemia, asthenia after severe illness, arrhythmias and other heart diseases and liver disease.[4]

Traditional Asian medicines

Medicinal use of the caterpillar fungus apparently originated in Tibet and Nepal. So far the oldest known text documenting its use was written in the late fourteen hundreds by the Tibetan doctor Zurkhar Nyamnyi Dorje (Wylie: Zur mkhar mnyam nyid rdo rje)[1439-1475]) in his text: Man ngag bye ba ring bsrel (“Instructions on a Myriad of Medicines”). A translation is available at Winkler.[19]

The first mention of Ophiocordyceps sinensis in traditional Chinese Medicine was in Wang Ang’s 1694 compendium of materia medica, Ben Cao Bei Yao.[20] In the 18th Century it was listed in Wu Yiluo‘s Ben cao cong xin (“New compilation of materia medica”).[21] No sources have been published to uphold widespread claims of “thousands of years of use in Chinese medicine” or use of “chong cao since the 7th Century Tang Dynasty in China”. The ethno-mycological knowledge on caterpillar fungus among the Nepalese people is documented byDevkota(2006) The entire fungus-caterpillar combination is hand-collected for medicinal use.

The fungus is a medicinal mushroom which is highly prized by practitioners of Tibetan medicine, Chinese medicine and traditional Folk medicines, in which it is used as an aphrodisiac and as a treatment for a variety of ailments from fatigue to cancer. In Chinese medicine it is regarded as having an excellent balance of yin and yang as it is apparently both animal and vegetable. Assays have found thatOphiocordyceps species produce many pharmacologically active substances. They are now cultivated on an industrial scale for their medicinal value. However, no one has succeeded so far in growing the larva cum mushroom artificially. The biological process that forms the Ophiocordyceps is still unknown and true cultivation has yet to be realized.[3] All artificial products are derived from mycelia grown on grains or in liquids.

According to Bensky et al. (2004), laboratory-grown C. sinensis mycelia have similar clinical efficacy and less associated toxicity. He notes a toxicity case of constipation, abdominal distension, and decreased peristalsis, two cases of irregular menstruation, and one case report ofamenorrhea following ingestion of tablets or capsules containing C. sinensis. In Chinese medicine C. sinensis is considered sweet and warm, entering the lung and kidney channels; the typical dosage is 3–9 grams.[22]

Research

Some work has been published in which Ophiocordyceps sinensis has been used to protect the bone marrow and digestive systems ofmice from whole body irradiation.[23] An experiment noted Ophiocordyceps sinensis may protect the liver from damage.[24] An experiment conducted with mice noted the mushroom may have an anti-depressant effect.[25] Researchers have noted that the caterpillar fungus has ahypoglycemic effect and may be beneficial for people with insulin resistance.[26][27][28][29][30] There is also experimental evidence of the supposed energizing effect of the fungus, as it has been shown to increase endurance through heightened ATP production in rats.[8]

A March 2013 study on Cordyceps Sinensis documented the medicinal fungus’ anti-inflammatory properties.[31] Scientists were able to show Cordyceps Sinensis’ ability to suppress interleukin-1b and interleukin-18 secretion by inhibiting both canonical and non-canonical inflammasomes. Inflammasomes have long been associated with auto-inflammatory diseases, such as gout. The study used a specific anamorphic mycelial form of Cordyceps Sinensis known as Hirsutella Sinensis.

Introduction to the Western world

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Ophiocordyceps sinensis

The Western world was largely unaware of Ophiocordyceps prior to 1993. The fungus dramatically caught the world’s eye due to the performance of three female Chinese athletes, Wang Junxia, Qu Yunxia, and Zhang Linli. These athletes broke five world records for 1,500, 3,000 and 10,000 meter dashes at the National Games in Beijing, China. The number of new world records set at a single track event attracted much attention and suspicion. Following the races, the women were expected by some to fail drug tests for anabolic steroids. However, the athletes’ tests revealed no illegal substances, and coach Ma Junren told the reporters that the runners were takingOphiocordyceps sinensis and turtle blood at his request. However for the 2000 Sydney Olympics, Ma Junren withdrew some of his athletes at the last minute. It was speculated that a new doping test would have revealed illegal substances, thus half a dozen Chinese field and track athletes were left at home.

Economics and impact

Many shops in downtown Lanzhouadvertise Dōng chóng xià cǎo (冬虫夏草) among other local specialties.

In rural Tibet, yartsa gunbu has become the most important source of cash income. The fungi contributed 40% of the annual cash income to local households and 8.5% to the GDP in 2004. Prices have increased continuously, especially since the late 1990s. In 2008, one kilogram traded for US$3,000 (lowest quality) to over US$18,000 (best quality, largest larvae). The annual production on the Tibetan Plateau was estimated in 2009 at 80–175 tons.[32] The Himalayan Ophiocordyceps production might not exceed a few tons.

In 2004 the value of a kilogram of caterpillars was estimated at about 30,000 to 60,000 Nepali rupees in Nepal, and about Rs 100,000 in India.[33] In 2011 the value of a kilogram of caterpillars was estimated at about 350,000 to 450,000 Nepali rupees in Nepal. A 2012 BBC article indicated that in north Indian villages a single fungus was worth Rs 150 (about £2 or $3), which is more than the daily wage of a manual laborer.[34]

According to Daniel Winkler, the price of Ophiocordyceps sinensis has risen dramatically on the Tibetan Plateau, basically 900% between 1998 and 2008, an annual average of over 20% (after inflation). However, the value of big sized caterpillar fungus has increased more dramatically than smaller size Cordyceps, regarded as lower quality.[20]

Because of its high value, inter-village conflicts over access to its grassland habitats has become a headache for the local governing bodies and in several cases people were killed. In November 2011, a court in Nepal convicted 19 villagers over the murder of a group of farmers during a fight over the prized aphrodisiac fungus. Seven farmers were killed in the remote northern district of Manang in June 2009 after going to forage for Yarchagumba. [35]

Its value gave it a role in the Nepalese Civil War, as the Nepalese Maoists and government forces fought for control of the lucrative export trade during the June–July harvest season.[36] Collecting yarchagumba in Nepal had only been legalised in 2001, and now demand is highest in countries such as China, Thailand, Vietnam, Korea and Japan. By 2002, the herb was valued at R 105,000 ($1,435) per kilogram, allowing the government to charge a royalty of R 20,000 ($280) per kilogram.

The search for Ophiocordyceps sinensis is often perceived to pose a threat to the environment of the Tibetan Plateau where it grows. While it has been collected for centuries and is still common in such areas, current collection rates are much higher than in historical times.

Ophiocordyceps producers like to perpetuate the story that unscrupulous harvesters insert twigs into the ascocarps of wild C. sinensis to increase their weight and therefore the price paid. A tiny twig is only used when the ascocarp is broken from the caterpillar, and has nothing to do with artificially increasing weight. Supposedly, at some point in the past, someone inserted lead wires with which to increase weight; however, each year hundreds of millions of specimens are harvested and this appears to have been a one-time occurrence.

Cultivated C. sinensis mycelium is an alternative to wild-harvested C. sinensis, and producers claim it may offer improved consistency. Artificial culture of C. sinensis is typically by growth of pure mycelia in liquid culture (in China) or on grains (in the West). The first time in Vietnam, Prof. Aca. Dr. Dai Duy Ban together with scientists and DAIBIO Company and DAIBIO Great Traditional Medicine Family Clinic discovered the Cordyceps sinensis as Isaria cerambycidae N.SP. to develop Fermentation DAIBIO Cordyceps Sinensis.[37]Ascocarps are not produced through in vitro cultivation.

Preparations: The seeds are collected after the apricot ripens in summer. They are then dried in the sun and pounded into pieces.Properties & Taste: Bitter, slightly warm and slightly toxic.Meridians: Lung and large intestine.

Functions: 1. To stop cough and relieve asthma; 2. To moisten the intestines and move stool.Indications & Combinations:1. Cough and asthma: a) cough due to invasion by exogenous pathogenic wind and heat Apricot seed (Xingren) is used with Mulberry leaf (Sangye) and Chrysanthemum flower (Juhua) in the formula Sang Ju Yin; b) cough due to dysfunction of the lungs caused by dryness and heatApricot seed (Xingren) is used with Mulberry leaf (Sangye), Tendrilled fritillary bulb (Chuanbeimu) and Glehnia root (Shashen) in the formula Sang Xing Tang; c) cough and asthma due to accumulated heat in the lungsApricot seed (Xingren) is used with Gypsum (Shigao) and Ephedra (Mahuang) in the formula Ma Xing Shi Gan Tang.2. Constipation due to dryness in the intestines: Apricot seed (Xingren) is used with Hemp seed (Huomaren) and Chinese angelica root (Danggui) in the formula Runchang Wan.Dosage: 3-10 g.Cautions & Contraindications: This herb is slightly toxic, so overdosing should be avoided. It should be used with caution in infants.

Bitter Apricot Seed ( Xingren ) 杏仁

Bitter Apricot Seed ( Xingren ) 杏仁 Toxicity & Cautions:

Bitter Apricot Seed ( Xingren ) 杏仁 contain hydrogen cyanide which is a strong toxin. Eating 20 to 30 piece may cause toxic reaction even death. The toxin can be hydrolyzed in cooking and can render it non toxic. It is not recommended for small children.

Properties
Taste: bitter; nature: slightly warm; slightly toxic.

Channels entered
Lung and Large Intestine.

Functions and indications
Stops coughing and calms wheezing, moistens the Intestines and frees the bowels. It is indicated for coughing and wheezing, sore throat andconstipation.

Common dosage
3-10g, decocted for a short time only.

Precautions and contraindications

As Xing Ren is slightly toxic, large dosages should be avoided, especially when treating infants.

In China, people who can afford to buy apricot as a fresh fruit generally throw the stones away. Servants and the less fortunate children gatherthe stones and sell them to collectors who use cheap labor to crack the shells (endocarp) and free the seeds (kernel) with the brown seed coat tightly covering the embryo (two cotyledons with the small radical and plumule).

In Chinese prescriptions, an apricot seed with the brown seed coat intact is called bei-xing-ren (northern apricot seed). All Chinese apothecaries keep a supply of apricot seeds in this state.

Detoxificated apricot seed: The major portion of the annual production of apricot seed is detoxified, processed by being first subjected to boiling water to loosen the seed coat, which can then be rubbed off by hand, followed by soaking the white cotyledons in cold water with several changes to eliminate the bitter element and to detoxify them. Then the detoxified white cotyledons are dried for the market. In Chinese prescriptions, this decoated and detoxified material is called nan-xing-ren (southern apricot seed) or tian-xing-ren (sweet apricot seed), which is also available in apothecaries. However, a greater portion of the detoxified material is used in pastry and for food.

Toxicity
The LD for intravenous injection of amygdalin in mice or rats is 25g/kg; for intraperitoneal injection, it is 8g/kg; and for oraladministration, it is O.6g/kg. Oral administration of 55 pieces (the equivalem of about 60g) of Ku Xing Ren, containing 1.8g of amygdalin, can cause death in humans. The main symptoms oftoxic reaction include a bitter taste in the mouth, dizziness, nausea, vomiting, pain in the abdomen, diarrhoea, agitation, vexation and restlessness, palpitations, and weakness of the limbs, and in severe cases, oppression in the chest, difficulty in breathing, loss of consciousness, a reduction in blood pressure and even coma. Ku Xing Ren should therefore not be used raw and overdosage must be avoided.